tbuckley/cabot-search huggingface dataset:
Extracellular Vesicle-Mediated Transfer of LncRNA <i>IGFL2-AS1</i> Confers Sunitinib Resistance in Renal Cell Carcinoma
Authors: Yihui Pan, Xuanxuan Lu, Guannan Shu, Junjie Cen, Jun Lu, Mi Zhou, Kangbo Huang, Jiaqi Dong, Jiaying Li, Haishan Lin, Hongde Song, Quanhui Xu, Hui Han, Zhenhua Chen, Wei Chen, Junhang Luo, Jinhuan Wei, Jiaxing Zhang
Journal: Cancer Research (2022)

Abstract Sunitinib resistance remains a serious challenge to the treatment of advanced and metastatic renal cell carcinoma (RCC), yet the mechanisms underlying this resistance are not fully understood. Here, we report that the long noncoding RNA IGFL2-AS1 is a driver of therapy resistance in RCC. IGFL2-AS1 was highly upregulated in sunitinib-resistant RCC cells and was associated with poor prognosis in patients with clear cell RCC (ccRCC) who received sunitinib therapy. IGFL2-AS1 enhanced TP53INP2 expression by competitively binding to hnRNPC, a multifunctional RNA-binding protein that posttranscriptionally suppresses TP53INP2 expression through alternative splicing. Upregulated TP53INP2 enhanced autophagy and ultimately led to sunitinib resistance. Meanwhile, IGFL2-AS1 was packaged into extracellular vesicles through hnRNPC, thus transmitting sunitinib resistance to other cells. N6-methyladenosine modification of IGFL2-AS1 was critical for its interaction with hnRNPC. In a patient-derived xenograft model of sunitinib-resistant ccRCC, injection of chitosan-solid lipid nanoparticles containing antisense oligonucleotide-IGFL2-AS1 successfully reversed sunitinib resistance. These findings indicate a novel molecular mechanism of sunitinib resistance in RCC and suggest that IGFL2-AS1 may serve as a prognostic indicator and potential therapeutic target to overcome resistance. Significance: Extracellular vesicle-packaged IGFL2-AS1 promotes sunitinib resistance by regulating TP53INP2-triggered autophagy, implicating this lncRNA as a potential therapeutic target in renal cell carcinoma.
Emollients for prevention of atopic dermatitis: 5‐year findings from the <scp>BEEP</scp> randomized trial
Authors: Lucy E. Bradshaw, Laura A. Wyatt, Sara J. Brown, Rachel H. Haines, Alan A. Montgomery, Michael R. Perkin, Sandra Lawton, Tracey H. Sach, Joanne R. Chalmers, Matthew J. Ridd, Carsten Flohr, Joanne Brooks, Richard Swinden, Eleanor J. Mitchell, Stella Tarr, Nicola Jay, Kim S. Thomas, Hilary Allen, Michael J. Cork, Maeve M. Kelleher, Eric L. Simpson, Stella T. Lartey, Susan Davies‐Jones, Robert J. Boyle, Hywel C. Williams
Journal: Allergy (2022)

Abstract Background The effectiveness of emollients for preventing atopic dermatitis/eczema is controversial. The Barrier Enhancement for Eczema Prevention trial evaluated the effects of daily emollients during the first year of life on atopic dermatitis and atopic conditions to age 5 years. Methods 1394 term infants with a family history of atopic disease were randomized (1:1) to daily emollient plus standard skin‐care advice (693 emollient group) or standard skin‐care advice alone (701 controls). Long‐term follow‐up at ages 3, 4 and 5 years was via parental questionnaires. Main outcomes were parental report of a clinical diagnosis of atopic dermatitis and food allergy. Results Parents reported more frequent moisturizer application in the emollient group through to 5 years. A clinical diagnosis of atopic dermatitis between 12 and 60 months was reported for 188/608 (31%) in the emollient group and 178/631 (28%) in the control group (adjusted relative risk 1.10, 95% confidence interval 0.93 to 1.30). Although more parents in the emollient group reported food reactions in the previous year at 3 and 4 years, cumulative incidence of doctor‐diagnosed food allergy by 5 years was similar between groups (92/609 [15%] emollients and 87/632 [14%] controls, adjusted relative risk 1.11, 95% confidence interval 0.84 to 1.45). Findings were similar for cumulative incidence of asthma and hay fever. Conclusions Daily emollient application during the first year of life does not prevent atopic dermatitis, food allergy, asthma or hay fever.
Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor–Mutated, <i>MET</i>-Amplified Non–Small Cell Lung Cancer: TATTON
Authors: Ryan J. Hartmaier, Aleksandra A. Markovets, Myung Ju Ahn, Lecia V. Sequist, Ji-Youn Han, Byoung Chul Cho, Helena A. Yu, Sang-We Kim, James Chih-Hsin Yang, Jong-Seok Lee, Wu-Chou Su, Dariusz M. Kowalski, Sergey Orlov, Song Ren, Paul Frewer, Xiaoling Ou, Darren A.E. Cross, Nisha Kurian, Mireille Cantarini, Pasi A. Jänne
Journal: Cancer Discovery (2022)

MET-inhibitor and EGFR tyrosine kinase inhibitor (EGFR-TKI) combination therapy could overcome acquired MET-mediated osimertinib resistance. We present the final phase Ib TATTON (NCT02143466) analysis (Part B, n = 138/Part D, n = 42) assessing oral savolitinib 600 mg/300 mg once daily (q.d.) + osimertinib 80 mg q.d. in patients with MET-amplified, EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) and progression on prior EGFR-TKI. An acceptable safety profile was observed. In Parts B and D, respectively, objective response rates were 33% to 67% and 62%, and median progression-free survival (PFS) was 5.5 to 11.1 months and 9.0 months. Increased antitumor activity may occur with MET copy number ≥10. EGFRm circulating tumor DNA clearance on treatment predicted longer PFS in patients with detectable baseline ctDNA, while acquired resistance mechanisms to osimertinib + savolitinib were mediated by MET, EGFR, or KRAS alterations. The savolitinib + osimertinib combination represents a promising therapy in patients with MET-amplified/overexpressed, EGFRm advanced NSCLC with disease progression on a prior EGFR-TKI. Acquired resistance mechanisms to this combination include those via MET, EGFR, and KRAS. On-treatment ctDNA dynamics can predict clinical outcomes and may provide an opportunity to inform earlier decision-making. This article is highlighted in the In This Issue feature, p. 1.
Practical Considerations for the Use of Circulating Tumor DNA in the Treatment of Patients With Cancer
Authors: Matthew G. Krebs, Umberto Malapelle, Fabrice André, Luis Paz-Ares, Martin Schuler, David M. Thomas, Gilad Vainer, Takayuki Yoshino, Christian Rolfo
Journal: JAMA Oncology (2022)

Importance Personalized medicine based on tumor profiling and identification of actionable genomic alterations is pivotal in cancer management. Although tissue biopsy is still preferred for diagnosis, liquid biopsy of blood-based tumor analytes, such as circulating tumor DNA, is a rapidly emerging technology for tumor profiling. Observations This review presents a practical overview for clinicians and allied health care professionals for selection of the most appropriate liquid biopsy assay, specifically focusing on circulating tumor DNA and how it may affect patient treatment and case management across multiple tumor types. Multiple factors influence the analytical validity, clinical validity, and clinical utility of testing. This review provides recommendations and practical guidance for best practice. Current methodologies include polymerase chain reaction-based approaches and those that use next-generation sequencing (eg, capture-based profiling, whole exome, or genome sequencing). Factors that may influence utility include sensitivity and specificity, quantity of circulating tumor DNA, detection of a small vs a large panel of genes, and clonal hematopoiesis of indeterminate potential. Currently, liquid biopsy appears useful in patients unable to undergo biopsy or where mutations detected may be more representative of the predominant tumor burden than for tissue-based assays. Other potential applications may include screening, primary diagnosis, residual disease, local recurrence, therapy selection, or early therapy response and resistance monitoring. Conclusions and Relevance This review found that liquid biopsy is increasingly being used clinically in advanced lung cancer, and ongoing research is identifying applications of circulating tumor DNA-based testing that complement tissue analysis across a broad range of clinical settings. Circulating tumor DNA technologies are advancing quickly and are demonstrating potential benefits for patients, health care practitioners, health care systems, and researchers, at many stages of the patient oncologic journey.
The Value and Impacts of Academic Public Health Departments
Authors: Paul C. Erwin, Julie H. Grubaugh, Stephanie Mazzucca-Ragan, Ross C. Brownson
Journal: Annual Review of Public Health (2022)

The academic health department (AHD) is a partnership between an academic institution and a governmental health agency. These partnerships are meant to provide mutual benefits that include opportunities for student field placements and internships, practice-informed curriculum, and practice-based research. The term academic health department dates back only to 2000, although there are several examples of academic–practice partnerships prior to that date. In addition to AHDs that have been established over the past two decades, other forms of academic–practice engagement provide similar mutual benefits, such as prevention research centers and public health training centers. Current research on AHDs explores how these partnerships matter regarding the outputs, outcomes, and impacts of the units that comprise them. This review also considers the most recent perspectives on how AHDs have responded to the COVID-19 pandemic and how they might advance public health's efforts to address structural racism and promote health equity.
Common Variable Immunodeficiency: More Pathways than Roads to Rome
Authors: Xiao P. Peng, Andrés Caballero-Oteyza, Bodo Grimbacher
Journal: Annual Review of Pathology Mechanisms of Disease (2022)

Fifty years have elapsed since the term common variable immunodeficiency (CVID) was introduced to accommodate the many and varied antibody deficiencies being identified in patients with suspected inborn errors of immunity (IEIs). Since then, how the term is understood and applied for diagnosis and management has undergone many revisions, though controversy persists on how exactly to define and classify CVID. Many monogenic disorders have been added under its aegis, while investigations into polygenic, epigenetic, and somatic contributions to CVID susceptibility have gained momentum. Expansion of the overall IEI landscape has increasingly revealed genotypic and phenotypic overlap between CVID and various other immunological conditions, while increasingly routine genotyping of CVID patients continues to identify an incredible diversity of pathophysiological mechanisms affecting even single genes. Though many questions remain to be answered, the lessons we have already learned from CVID biology have greatly informed our understanding of adaptive, but also innate, immunity.
Allogeneic hematopoietic cell transplantation in patients with chronic phase chronic myeloid leukemia in the era of third generation tyrosine kinase inhibitors: A retrospective study by the chronic malignancies working party of the <scp>EBMT</scp>
Authors: Yves Chalandon, Giulia Sbianchi, Luuk Gras, Linda Koster, Jane Apperley, Jenny Byrne, Urpu Salmenniemi, Henrik Sengeloev, Mahmoud Aljurf, Grzegorz Helbig, Francesca Kinsella, Goda Choi, Péter Reményi, John A. Snowden, Marie Robin, Stig Lenhoff, Stephan Mielke, Jakob Passweg, Annoek E. C. Broers, Nicolaus Kröger, Zeynep Arzu Yegin, Sen Mui Tan, Patrick J. Hayden, Donal P. McLornan, Ibrahim Yakoub‐Agha
Journal: American Journal of Hematology (2022)

Abstract Following the introduction of tyrosine kinase inhibitors (TKI), the number of patients undergoing allogeneic hematopoietic cell transplantation (allo‐HCT) for chronic phase (CP) chronic myeloid leukemia (CML) has dramatically decreased. Imatinib was the first TKI introduced to the clinical arena, predominantly utilized in the first line setting. In cases of insufficient response, resistance, or intolerance, CML patients can subsequently be treated with either a second or third generation TKI. Between 2006 and 2016, we analyzed the impact of the use of 1, 2, or 3 TKI prior to allo‐HCT for CP CML in 904 patients. A total of 323‐, 371‐, and 210 patients had 1, 2, or 3 TKI prior to transplant, respectively; imatinib ( n = 778), dasatinib ( n = 508), nilotinib ( n = 353), bosutinib ( n = 12), and ponatinib ( n = 44). The majority had imatinib as first TKI ( n = 747, 96%). Transplants were performed in CP1, n = 549, CP2, n = 306, and CP3, n = 49. With a median follow‐up of 52 months, 5‐year OS for the entire population was 64.4% (95% CI 60.9–67.9%), PFS 50% (95% CI 46.3–53.7%), RI 28.7% (95% CI 25.4–32.0%), and NRM 21.3% (95% CI 18.3–24.2%). No difference in OS, PFS, RI, or NRM was evident related to the number of TKI prior to allo‐HCT or to the type of TKI ( p = ns). Significant factors influencing OS and PFS were &gt; CP1 versus CP1 and Karnofsky performance (KPS) score &gt; 80 versus ≤80, highlighting CP1 patients undergoing allo‐HCT have improved survival compared to &gt;CP1 and the importance of careful allo‐HCT candidate selection.
Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study
Authors: Vijay Maruti Patil, Vanita Noronha, Nandini Menon, Rahul Rai, Atanu Bhattacharjee, Ajay Singh, Kavita Nawale, Shweta Jogdhankar, Rupali Tambe, Sachin Dhumal, Riddhi Sawant, Mitali Alone, Devanshi Karla, Zoya Peelay, Shruti Pathak, Arun Balaji, Suman Kumar, Nilendu Purandare, Archi Agarwal, Ameya Puranik, Abhishek Mahajan, Amit Janu, Gunjesh Kumar Singh, Neha Mittal, Subhash Yadav, Shripad Banavali, Kumar Prabhash
Journal: Journal of Clinical Oncology (2022)

The regimens approved for the treatment of advanced head and neck squamous cell carcinoma are accessible to only 1%-3% of patients in low- and middle-income countries because of their cost. In our previous study, metronomic chemotherapy improved survival in this setting. Retrospective data suggest that a low dose of nivolumab may be efficacious. Hence, we aimed to assess whether the addition of low-dose nivolumab to triple metronomic chemotherapy (TMC) improved overall survival (OS).This was a randomized phase III superiority study. Adult patients with recurrent or newly diagnosed advanced head and neck squamous cell carcinoma being treated with palliative intent with an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Patients were randomly assigned 1:1 to TMC consisting of oral methotrexate 9 mg/m2 once a week, celecoxib 200 mg twice daily, and erlotinib 150 mg once daily, or TMC with intravenous nivolumab (TMC-I) 20 mg flat dose once every 3 weeks. The primary end point was 1-year OS.One hundred fifty-one patients were randomly assigned, 75 in TMC and 76 in the TMC-I arm. The addition of low-dose nivolumab led to an improvement in the 1-year OS from 16.3% (95% CI, 8.0 to 27.4) to 43.4% (95% CI, 30.8 to 55.3; hazard ratio, 0.545; 95% CI, 0.362 to 0.820; P = .0036). The median OS in TMC and TMC-I arms was 6.7 months (95% CI, 5.8 to 8.1) and 10.1 months (95% CI, 7.4 to 12.6), respectively (P = .0052). The rate of grade 3 and above adverse events was 50% and 46.1% in TMC and TMC-I arms, respectively (P = .744).To our knowledge, this is the first-ever randomized study to demonstrate that the addition of low-dose nivolumab to metronomic chemotherapy improved OS and is an alternative standard of care for those who cannot access full-dose checkpoint inhibitors.
Health Benefits and Cost-Effectiveness of Children's Oncology Group Breast Cancer Screening Guidelines for Chest-Irradiated Hodgkin Lymphoma Survivors
Authors: F. Lennie Wong, Janie M. Lee, Wendy M. Leisenring, Joseph P. Neglia, Rebecca M. Howell, Susan A. Smith, Kevin C. Oeffinger, Chaya S. Moskowitz, Tara O. Henderson, Ann Mertens, Paul C. Nathan, Yutaka Yasui, Wendy Landier, Gregory T. Armstrong, Leslie L. Robison, Smita Bhatia
Journal: Journal of Clinical Oncology (2022)

PURPOSE To evaluate the outcomes and cost-effectiveness of the Children's Oncology Group Guideline recommendation for breast cancer (BC) screening using mammography (MAM) and breast magnetic resonance imaging (MRI) in female chest-irradiated childhood Hodgkin lymphoma (HL) survivors. Digital breast tomosynthesis (DBT), increasingly replacing MAM in practice, was also examined. METHODS Life years (LYs), quality-adjusted LYs (QALYs), BC mortality, health care costs, and false-positive screen frequencies of undergoing annual MAM, DBT, MRI, MAM + MRI, and DBT + MRI from age 25 to 74 years were estimated by microsimulation. BC risks and non-BC mortality were estimated from female 5-year survivors of HL in the Childhood Cancer Survivor Study and the US population. Test performance of MAM and MRI was synthesized from HL studies, and that of DBT from the general population. Costs (2017 US dollars [USD]) and utility weights were obtained from the medical literature. Incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS With 100% screening adherence, annual BC screening extended LYs by 0.34-0.46 years over no screening. If the willingness-to-pay threshold to gain a quality-adjusted LY was ICER &lt; $100,000 USD, annual MAM at age 25-74 years was the only cost-effective strategy. When nonadherence was taken into consideration, only annual MAM at age 30-74 years (ICER = $56,972 USD) was cost-effective. Supplementing annual MAM with MRI costing $545 USD was not cost-effective under either adherence condition. If MRI costs were reduced to $300 USD, adding MRI to annual MAM at age 30-74 years could become more cost-effective, particularly in the reduced adherence condition (ICER = $133,682 USD). CONCLUSION Annual BC screening using MAM at age 30-74 years is effective and cost-effective in female chest-irradiated HL survivors. Although annual adjunct MRI is not cost-effective at $545 USD cost, it could become cost-effective as MRI cost is reduced, a plausible scenario with the emergent use of abbreviated MRI.
Landscape of MicroRNA Regulatory Network Architecture and Functional Rerouting in Cancer
Authors: Xu Hua, Yongsheng Li, Sairahul R. Pentaparthi, Daniel J. McGrail, Raymond Zou, Li Guo, Aditya Shrawat, Kara M. Cirillo, Qing Li, Akshay Bhat, Min Xu, Dan Qi, Ashok Singh, Francis McGrath, Steven Andrews, Kyaw Lwin Aung, Jishnu Das, Yunyun Zhou, Alessia Lodi, Gordon B. Mills, S. Gail Eckhardt, Marc L. Mendillo, Stefano Tiziani, Erxi Wu, Jason H. Huang, Nidhi Sahni, S. Stephen Yi
Journal: Cancer Research (2022)

Abstract Somatic mutations are a major source of cancer development, and many driver mutations have been identified in protein coding regions. However, the function of mutations located in miRNA and their target binding sites throughout the human genome remains largely unknown. Here, we built detailed cancer-specific miRNA regulatory networks across 30 cancer types to systematically analyze the effect of mutations in miRNAs and their target sites in 3′ untranslated region (3′ UTR), coding sequence (CDS), and 5′ UTR regions. A total of 3,518,261 mutations from 9,819 samples were mapped to miRNA–gene interactions (mGI). Mutations in miRNAs showed a mutually exclusive pattern with mutations in their target genes in almost all cancer types. A linear regression method identified 148 candidate driver mutations that can significantly perturb miRNA regulatory networks. Driver mutations in 3′UTRs played their roles by altering RNA binding energy and the expression of target genes. Finally, mutated driver gene targets in 3′ UTRs were significantly downregulated in cancer and functioned as tumor suppressors during cancer progression, suggesting potential miRNA candidates with significant clinical implications. A user-friendly, open-access web portal (mGI-map) was developed to facilitate further use of this data resource. Together, these results will facilitate novel noncoding biomarker identification and therapeutic drug design targeting the miRNA regulatory networks. Significance: A detailed miRNA–gene interaction map reveals extensive miRNA-mediated gene regulatory networks with mutation-induced perturbations across multiple cancers, serving as a resource for noncoding biomarker discovery and drug development.
Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression
Authors: Carina Seah, Michael S. Breen, Tom Rusielewicz, Heather N. Bader, Changxin Xu, Christopher J. Hunter, Barry McCarthy, P. J. Michael Deans, Mitali Chattopadhyay, Jordan Goldberg, Saunil Dobariya, Frank Desarnaud, Iouri Makotkine, Janine D. Flory, Linda M. Bierer, Migle Staniskyte, Lauren Bauer, Katie Brenner, Geoff Buckley-Herd, Sean DesMarteau, Patrick Fenton, Peter Ferrarotto, Jenna Hall, Selwyn Jacob, Travis Kroeker, Gregory Lallos, Hector Martinez, Paul McCoy, Frederick J. Monsma, Dorota Moroziewicz, Reid Otto, Kathryn Reggio, Bruce Sun, Rebecca Tibbets, Dong Woo Shin, Hongyan Zhou, Matthew Zimmer, Scott A. Noggle, Laura M. Huckins, Daniel Paull, Kristen J. Brennand, Rachel Yehuda
Journal: Nature Neuroscience (2022)

Abstract Post-traumatic stress disorder (PTSD) can develop following severe trauma, but the extent to which genetic and environmental risk factors contribute to individual clinical outcomes is unknown. Here, we compared transcriptional responses to hydrocortisone exposure in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and peripheral blood mononuclear cells (PBMCs) from combat veterans with PTSD ( n = 19 hiPSC and n = 20 PBMC donors) and controls ( n = 20 hiPSC and n = 20 PBMC donors). In neurons only, we observed diagnosis-specific glucocorticoid-induced changes in gene expression corresponding with PTSD-specific transcriptomic patterns found in human postmortem brains. We observed glucocorticoid hypersensitivity in PTSD neurons, and identified genes that contribute to this PTSD-dependent glucocorticoid response. We find evidence of a coregulated network of transcription factors that mediates glucocorticoid hyper-responsivity in PTSD. These findings suggest that induced neurons represent a platform for examining the molecular mechanisms underlying PTSD, identifying biomarkers of stress response, and conducting drug screening to identify new therapeutics.
SUSD2 suppresses CD8+ T cell antitumor immunity by targeting IL-2 receptor signaling
Authors: Bao Zhao, Weipeng Gong, Anjun Ma, Jianwen Chen, Maria Velegraki, Hong Dong, Zihao Liu, Lingling Wang, Tamio Okimoto, Devin M. Jones, Yu L. Lei, Meixiao Long, Kenneth J. Oestreich, Qin Ma, Gang Xin, David P. Carbone, Kai He, Zihai Li, Haitao Wen
Journal: Nature Immunology (2022)